Halo-disulfamylanilines



Unit d S es P t n &

3,619,245 Patented Jan. 30, 1962 k t 3,019,245 t HALO-DISULFAMYLANILINES Frederick C. Novello, Berwyn, Pa., assignor to Merck &

Co., Inc., Rahway, N. a corporation of New Jersey No Drawing. Original application Feb. 7, 1957, Ser. No. 638,701. Divided and this application Nov. 23, 1959, Ser. No. 854,565

,7 7 Claims. (Cl. 260--397.7)

I This invention is concerned with novel disulfamylaniline compounds having the general structural formula and their non-toxic salts, wherein R is halogen; R is hydrogen or lower alkyl having advantageously fromlto carbon atoms; R is hydrogen, a lower alkyl radical having advantageously from 1 to 5' carbon atoms, a lower alkanoyl advantageously a straight or branched chain alkanoyl radical having from '1' to 12 carbon atoms such the preparation of these compounds can be illustrated as follows:

.113 J 11 R6 SO;N\

N S O: R5

R III 1. Ammonia or an amino 2. Acid chloride or anhydride as theformyl, acetyl, c aproyl, .capryl, lauroyl, and the like is an unsubstituted or substituted amino radical and if substituted, R and R being either alike or dissimilar radicals selected respectively from lower alkyl either straight or branched chain and having advantageously from 1 to 6 carbon atoms, lower alkanoyl having preferably from 1 to 3 carbon atoms or can represent a heterocyclic ring such as 5- or fi-mem'bered ring selected from the l-pyrrolidyl, l-piperidyl, 4-morpholinyl and the like radicals.

The new compounds of this invention are useful chemotherapeutic agents principally because of their diuretic and/or natriuretic properties. The compounds can be administered in therapeutic dosages in conventional vehicles as in the form of a tablet as these compounds are effective upon oral administration as well as upon injec- Acid chloride or anhydride 1{\T R3 M I A l'lllIlOlllB -SO2C1 (mail 018 Amine a R R\ SO2N\ /NS 05 R R v 1 Few of the disulfonyl chloride compounds II, are known, and those which have not been described in the literature can be prepared readily by chlorosulfonation of the selected aniline compound I, preferably in the presence of an alkali metal halide, for example sodium, potassium-or lithium chloride. For all practical purposes, sodiumchloride can be used as it is readily available, cheap, and in its presence the reaction proceeds quite smoothly. As the reaction between these ingredients generally is quite vigorous, it is preferred to add the aniline derivative to the chlorosulfonic acid dropwise withstirring and cooling. After all of the aniline derivative has been added, the alkali metal chloride is added in small portions to allow for the evolution of hydrogen chloride at a modcrate rate. Following this, the mixture is heated at between about 100-200 C. preferably in an oil bath.

tion. As the compounds of this invention also are readily soluble in a dilute alkaline medium and in polyethylene glycol solutions, injectable solutions can be prepared by dissolving the desired compound in the selected medium to which preservatives can be added if desired.

The new compounds of this invention also are useful in preparing novel benzothiadiazine-l,l-dioxide compounds which also possess diuretic and/or natriuretic properties and which are the subject of my co-pending US. patent application Serial No. 582,082, filed by myself, Frederick C. Novello, May 2, 1956, and now US. Patent 2,809,194, of which the present-application is a continuation-in-part.

The disulfamylaniline derivatives of this invention can be prepared by a variety of methods. Two processess which have been found to be particularly well adapted to The disulfonyl chloride II, thus obtained then can be converted to the disulfamyl derivative III, by treatment with-ammonia or a primary or secondary amine by well known methods. If desired, following the reaction with ammonia or a primary or secondary amine the resulting product can be reacted with the desired acylating agent advantageously by heating on a steam bath to form the corresponding acylated aniline compound. The acylating agent can be any of the agents described below for this purpose. 7

Alternatively, the disulfonyl chloride compound II, can be acylated with an organic acid chloride or anhydride, the acid advantageously being selected from a'lower alkanoic acid such as acetic acid, propionic acid, caproic acid, capric acid, stearic acid and the like, or a mononuclear aryl-monocarboxylic acid or a mononuclear aryllower alkanoic acid such as benzoic acid, phenylacetic acid, phenylpropionic acid, cinnamic acid, and the like. This reaction proceeds quite smoothly with moderate heating on the steam bath yielding the N-acyl-disulfonyl chloride derivative IV.

' The acylated compound IV,'then can be converted to the corresponding amide'by treatment with a'rnmcniaor a primary or secondary amine by the method described above for conversion of thedisulfonyl chloride, com: pound II-, to the disulfamyl compoundlII.

The desired salt of the disulfamylaniline compounds of this invention whereinR or R is hydrogen can be prepared advantageously bydissolving the selected compound in an aqueous or alcoholic solution of an alkali metal hydroxide, and if desired,-isolating the salt by evaporating the solvent. of the conventional alkali metal salts such as sodium, potassium, lithium or the like salt, can be prepared by this" method or by other round bottom, 3 ne'cked flask cooled in an ice bath. Sodium chloride (350 g.) was added portionwise over a period of 1-2 hours and the mixture then heated gradually in an'oil bath to 150. C. After 3 hours at 150- 160 C., the flask was cooled thoroughly in an ice bath and the contents treated with a liter of cold water. The product was extracted with ether and the extract washed with water and dried over sodium sulfate. moval of ether on the steam bath, the residual S-chloroaniline-2,4-disulfonyl chloride, which may be crystallized from benzene-hexane, M.P. 130-132 C., was cooled in After rewas added portionwise over 2 hours and the mixture thenheated in an oil bath at 150 Cpfor 3 hours. After thorough cooling in an ice -bath, the reaction mixture was treated with one liter of ice water. The product was taken up in ether, washed with water and dried. After removal of solvent on the steam bath, the residue was cooled in an ice bath and treated with 150 ml. of 28% ammonium hydroxide. After the initial vigorous reaction had subsided, the mixture was warmed on the steam bath for 1 hour, cooled and the precipitate collected on the filter. Crystallization from dilute alcohol gave 5-bromo-2,4-disulfamylanilineas colorless needles, M.P 265-267 C.

alysis for 'C H BrN O S r calculated: C, 21.82; H, 2.44j N, 12.73. Found: C, 22.04; H, 2.72; N, 12.72. EXAMPLE 4 2,4-disulfamyI-S-methylaniline By replacing them-bromoaniline employed in Example 3 by an equimolecular quantity of m-toluidine (53.5 g.) and following substantially the same procedure described in Example 3, 2,4-disulfamyl-5-methylaniline was obtained as colorless needles, melting point an ice bath and treated with 150 ml. of 28% ammonium hydroxide in a 2-liter Erlenmeyer flask. The mixture was heated on the steam bath for 1 hour, cooled and the product collected on the filter, washed with water and dried. Up'on' crystallization from dilute alcohol, S-chloro-2,4-disulfamylaniline was obtained as colorless needles, M.P. 251-252" C.

Analysis for C H ClN O S .--Calculated: C, 25.22; H, 2.82; N, 14.71. Found: C, 25.48; H, 2.81; N, 14.68.

EXAMPLE 2 6-chlore-2,4-disulfamylaniline o-Chloroacetanilide (15.2 g.) was added portionwise to 120 ml. chlorosulfonic acid at room temperature followed by portionwise addition of 100 g. of sodium chloride over 1 hour. The mixture then was heated gradually to 150 C. in an oil bath over a V2 hour period and then maintained at 150 C. for 2 hours. After cooling thoroughly in an ice bath, the reaction mixture was treated with 500 ml. of ice water and the product taken up in ether and washed with water and dried over sodium sulfate. After removal of ether by evaporation on the steam bath, the residual disulfonyl chloride was cooled in an ice bath and treated with 50 ml. of 28% ammonium hydroxide. The ammoniacal solution was heated on the steam bath for 1 hour, cooled and the product collected on the filter. Crystallization from dilute alcohol gave 6-chloro-2,4-disulfamylaniline as colorless needles, M.P. 242-244 C.

Analysis for C H ClN 0 S .Calculated: C, 25.22; H, 2.82; N, 14.71. Found: C, 25.52; H, 2.75; N, 14.59.

EXAMPLE 3 5-brom0-2,4-disulfamylaniline m-Bromoaniline (86 g., 0.5 mole) was added dropwise over a period of 1 hour to 375 ml. of chlorosulfonic acid cooled in an ice bath. Sodium chloride (350 a.)

-'Analysis for C H N 'O4S .-'Calculated: c, 3159,11, 4.18; N, 15.84. Found: 0, 31.68; H, 3.97; N, 15.84.

' EXAMPLE 5 4-chl0r0-2,S-disulfamylaniline By replacing the m-bromoaniline employed in Example 3 by an equimolecular quantity of S-arninochlorobenzenesulfonic acid, and following substantially the-same procedure described in Example 3, there was obtained 4 ehloro 2,5 disulfamylaniline as colorless needles, M.P. 289-290" C. 1

Analysis for C H C1N O S .Calculated: C, 25.22; H, 2.82; N, 14.71. Found: C, 25.51; H, 2.88; N, 14.58.

EXAMPLE 6 2,4-disulfamyl-5-methoxyaniline V Chlorosulfonic acid (150 ml.) was added dropwis over 30 minutes with stirring to 24.6 g. (0.2 mole) of m-anisidine cooled in an ice bath. After addition of chlorosulfonic acid was complete, 140 g. of sodium chloride was added portionwise over 1 hour. The mixture was heated for 2 hours on the steam bath and then for 3 hours in an oil bath, ISO-160 C., cooled thoroughly in an ice bath and treated with 500 ml. of ice water. The product was taken up in ether, washed with water, dried and the solvent evaporated on the steam bath. The residue was cooled in an ice bath and treated with ml. of 28% ammonium hydroxide. The precipitate was collected on the filter, washed with water and recrystallized from water to give 2,4-disulfamylmethoxyaniline as colorless needles, M.P. 252253 C. Analysis for C H N O S .Calculated: C, 29.89; H, 3.94; N, 14.94. Found: C, 30.12; H, 4.09; N, 14.93.

chlorosulfonic acid, g. of sodium chloride was added portionwise with stirring over 1 hour. After heating at C. for 2 hours, the reaction mixture was cooled in ice, treated with 1500 ml. of ice water and the product extracted with ether. The ethereal extract was dried over anhydrous sodium sulfate, filtered and evaporated to dryness on the steam bath. The residue was cooled in an ice bath and treated with 100 ml. of 28% ammonium hydroxide. After heating on the steam bath for one hour, the reaction mixture was cooled and the solid collected on the filter. Recrystallization from water gave 2,4-disulfamyl-5-nitroaniline as yellow needles, M.P. 260-262 C.

EXAMPLE 8 -amin02,4-disulfamylaniline EXAMPLE "9' 5 -chloro-2,4-disu lfamylacetanilide 5-chloroaniline-2,4-disulfonyl chloride (3.8 g.), prepared as described in Example 1, was dissolved in ml.

acetic anhydride and after V2 hour at room temperature cooled in ice and the product collected on the filter. After crystallization from a mixture of benzene-hexane, 5- chloroacetanilide-2,4-disulfonyl chloride was obtained and, after separation by filtration, was added portionwise to 50 ml. of liquid ammonia and the ammonia allowed to evaporate at room temperature. The residue was dissolved in 10 ml. of Water, acidified with 5 ml. of concentrated hydrochloric acid, and the crystalline product collected on the filter. Recrystallization from water gave 5-chloro-2,4-disulfamylacetanilide as colorless needles, M.P. 261-262 C. (dec.).

Analysis for C H ClN O5S .-Calculated: C, 29.31; H, 3.08; N, 12.82. Found: C, 29.49; H, 3.25; N, 12.85.

EXAMPLE 10 N -benzOEYl-5 -ch l arc-2,4-disulfamy [aniline M.P. 266 C. (dec.).

Analysis for C H ClN O S .Calculated: c, 40.05;

H, 3.10; N, 10.78. Found: C, 39.96; H, 3.47; N, 10.68.

EXAMPLE 11 I N-butyryZ-S-chloro-2,4-disulfamylaniline A solution of 5.4 g. of 5-chloroanilihe-Z,4-disulfonyl chloride, prepared as described in Example 1, in a mixture of 10 ml. of butyric anhydride and 10 ml. of benzene was allowed to stand at room temperature for 1 hour. After cooling in an ice bath, the crystalline product was collected and crystallized from a mixture of benzenehexane to give N-butyryl-5-chloroaniline-2,4-disulfonyl chloride as colorless needles, M.P. 121-122 C. The thus obtained disulfonyl chloride (9.9 g.) was added portionwise to excess liquid ammonia (100 ml.) and allowed to evaporate to dryness at room temperature. The residue was treated with water and the product collected on the filter. Recrystallization from aqueous alcohol yielded N butyryl-5-chloro-2',4-disulfamylaniline.

amyD-N-formylaniline as colorless 5. EXAMPLE 12 N caproyl-S -chl0r0-2,4 -disulftzmylaniline 5-chloroaniline-2,4-disulfony1 chloride (5 g.), prepared as described in Example 1, was dissolved in 10 m1. of n-caproic anhydride by warming gently on the steam bath and then allowed to stand at room temperature for" 2 hours. The crystalline product formed was collected and recrystallized from hexane to give N-caproyl-S- chloroaniline-2,4-disulfonyl chloride as colorless needles, M.P. 9l-93 C. The disulfonyl chloride thus obtained (9.9 g.) was added portionwise to 50 ml. of liquid am= monia. The solution was allowedto evaporate to dryness at room temperature and the residual solid then was treated with 50 ml. of water and the product collected on the filter. Recrystallization from aqueous alcohol af forded N-caproyl-S-chloro-Z,4-disulfamylaniline as colorless needles, M.P. 213-215 C.

EXAMPLE 13 2,4-disulfamyl-5-flu0m-ZlT-phenylacetylaniline cess liquid ammonia and allowed to evaporate to dryness at room temperature gave 2,4-disulfamyl-5-fluoro-N- phenylacetylaniline.

EXAMPLE 14 5-chlora-2,4-di-(N-methylsulfamyl) aniline 5-chloroaniline-2,4-disulfonyl chloride (6.6 g.)., prepared as described in Example 1, was added portionwise to 40% aqueous methylamine (50 ml.). After heating on the steam bath for 1 hour, the reaction. mixture was cooled and the crystalline solid collected on the filter. Recrystallization from aqueous alcohol gave 5-chloro- 2,4-di-(N-methylsulfamyl) aniline as colorless needles, M.P. 1755-178 C.

Analysis for C H clN O S .Calculated: C, 30.62; H, 3.86; N, 13.39. Found: C, 30.85; H, 3.81; N, 13.34.

EXAMPLE '15 5 -chl0r0-2,4-di-(N -methy lsulfamyl -N -f0rmylaniline A mixture of 5-ohloro-2,4-di-(N-meth ylsulfiamryl) aniline (2.8 g.), prepared as described in Example 14, and ethyl orthoform-ate (4 ml.) was heated at -130 C. for one hour and then for an additional 15 minutes at C. Upon cooling, a solid residue was obtained which was separated by filtration and recrystallized from aqueous alcohol to give 5-chlo-ro-2,4-di-(N-methylsulfplates, M.P. 192- 195 C.

Analysis for C H ClN O 'S .-Calculated: C, 31.63; H, 3.54; N, 12.29. Found: C, 31.99; H, 3.68; N, 12.29.

EXAMPLE l6 5 -chl0ro-2 ,4 -di-(N -acetylsulfamyl acetanilide A mixture of 5-ohloro-2,4-disulfamylaniline (2.9 :g.) prepared as described in Example 1, and acetic anhydride (10 ml.) was treated with two drops of concentrated sul- EXAMPLE 17 5 -clzloro-2,4-di- (1 -piperidinylsulfnyl aniline A solution of -chloroauiline-2,4-dis-ulfonyl chloride (9.7 g.),- prepared as described in Example 1, in benzene 200 ml.) was added dropwise over minutes to piperi dine (50 ml). After heating on the steam bath for 3 hours, themixture was cooled and washed with two 50 ml. portions of water, one 50 portion of dilute hydrochloric acid and one 50 ml.'porti0n of water. The benzene solution was dried over sodium sulfate and concentrated to dryness in vacuo. Recrystallization of the residue from ethanol aflorded 5-chloro-2,4-di-(l-piperidylsulfonyl) aniline, as colorless needles, M.P. 162-164 C.

3 .Analysis for C H ClN O S .-Calculated: C, 45.75, H, 5.76; N, 10.00. Found: C, 46.05; H, 5.67; N, 40.00.

EXAMPLE 1s 5-chloro-2,4-di-(N,N-dirnethylsulfamyl) aniline scribed in Example 1 there is obtained 5-chloro-2,4-disulfamyl-N-methylaniline.

a EXAMPLE 20 A 5-butyl-2,4-di-(N-n-butylsulfamyl) -N,N-laur0ylpropylaniline By replacing the m-chloroaniline employed in Example 1 by an equimolecular quantity of m-butyl-N-propylaniline and following substantially the same procedure described for the chlorosul fonation of the aniline derivative there described, there is obtained S-butyl-N-propy-laniline- 2,4-disulfony1 chloride. Five grams of the thus obtained disulfonyl chloride is dissolved in lauroyl chloride (10 ml.) and heated briefly on the steam bath. The reaction mixture then was allowed to cool to room temperature and the solid product thus formed collected on the filter. After crystallization from a mixture of benzene-hexane, 5-butyl- N,N-lauroylpropylaniline-2,4 disulfonyl chloride is obtained and the disulfonyl chloride added portionwise to n-butylamine (50 ml.) and heated for approximately one hour on the steam bath. After cooling to room temperature, the solid product is collected on the filter, washed with water and crystallized from a mixture of alcohol and water yielding 5-butyl-2,4-d-i-(N-n-butylsulfamyl) -N N- lanroylpropylaniiine.

EXAMPLE 21 2,4-di-(N,N-n-butylethylsulfamyl) -5-meihylaniline By replacing the m-chloroaniline employed in Example 1 by an equim-olecular quantity of m-toluidine and following substantially the same procedure described for the chlorosulfonation of the aniline derivative there described, there is obtained 5-methylaniline-2,4-disulfonyl chloride. Five grams of the thus obtained disulfonyl chloride then is added portio-nwise to n-butylethylamine and heated for approximately one hour on the steam bath. After cooling to room temperature the product is collected on the filter and washed with water yielding 2,4-di-(N,N-n-butylethylsulfamyD-S-methylaniline.

- ,EXAMPLEZZ 5 -prop0xy-2,4-ai-(4-m0rpholinylsulf0nyl -N -butylaniline EXAMPLE 23 2,4-di-(N,N,-dimethylsnlfamyl) 5-pfopoxy-N-cinnamoylaniline By replacing the m-chloroaniline employed in Example 1 by an equi'molec'ular' quantity of m-propoxvaniline and following substantially the same procedure described for the chlorosulfonation of the aniline derivative there described, there is obtained S-propoxyaniline-Z,4-disulfonyl chloride. Five grams of the thus obtained disulfonyl chloride is dissolved in cinnamoyl chloride (10 ml.) and heated briefly on the steam bath. The reaction mixture then is allowed to cool to room temperature and the solid product thus formed collected on the filter. After crystallization from a mixture of benzenehexane, S-propoxy-N- cinnamoylaniline 2,4 d-isulfonyl chloride is obtained. After separation by filtration, the disulfonyl chloride is added portionwise to 25% aqueous dimethylamine (50 ml.) and heated for approximately one hour on the steam bath. After cooling to room temperature, the solid product is collected on the filter and washed with water yielding 2,4-di-(N,N-dimethylsulfa-myl)-5-propoxy-N cinnamoylaniline.

EXAMPLE 24 Sodium salt of 5-chlor0-2,4-disulfamylaniline S-chloro-2,4-disulfamylaniline, obtained as described in Example 1, is dissolved in alcoholic sodium hydroxide The 5-chloro-2,4-disulfamylaniline is granulated with the starch paste and while moist passed through a No. 14 screen, dried at 45 C. for 20 hours and then passed three times through a No. 14 screen. The starch then is passed through a No. bolting cloth onto the granulation and all ingredients are blended thoroughly. Then the mag nesium stearate is passed through a No. 90 bolting cloth onto the granulation and these ingredients are blended after which the granulation is compressed into tablets using a fiat, beveled, scored punch having a thickness of 0205:0005" yielding 1,000 tablets, each Weighing 0.543 grams and having a hardness of 6 kgs. measured by the Monsanto Chemical Company Tablet Hardness Tester Apparatus, and a disintegration time of 5 minutes when tested on the USP Tablet Disintegrating Apparatus (U.S. Pharmacopeia, 15th edition, page 937).

While the above examples describe the preparation of certain illustrative compounds embraced by the general structure see column 1 lines 12-20 and a certain specific dosage form suitable for administering the novel compounds of this invention in human therapy, it is to be understood that the invention is not to be limited by these examples or by the specific reaction conditions described for the preparation of the compounds or by the specific ingredients in the pharmaceutical preparation, but is understood to embrace variations and modifications falling within the scope of the appended claims.

This application is a division of my copending United States patent application, Serial No. 638,701 which was filed February 7, 1957, and now abandoned.

What is claimed is:

:1. Disulfamylaniline derivatives selected from the group consisting of (1) compounds having the formula and (2) their non-toxic alkali metal salts, wherein the radical SO N-R R is attached to a position selected 30 from 4 and 5, and the Hal is attached to one of the unsubstituted positions selected from 6, 5 and 4; Hal is halogen; R is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen, lower alkyl, lower alkanoyl, benzoyl and phenyl-lower alkanoyl; and R and R respectively is selected from the group consisting of hydrogen, lower alkanoyl, lower alkyl and lower alkyl which are linked to form with the N-atom to which they are attached l-piperidyl, 4-morpholinyl and l-pyrroliydyl.

2. Disulfamylaniline compounds having the formula NH: Hal H:NSO1 soiNm wherein Hal is halogen attached to a position selected from 6 and 5.

3. 5-chloro-2,4-disulfamylaniline. 4. 6-chloro-2,4-disulfamylaniline. 5. Disulfamylaniline compounds having the formula wherein Hal is halogen attached to a position selected from 6 and 5 and Ac is lower alkanoyl.

6. N-caproyl-S-chloro-2,4-disulfamylaniline.

7. N-butyryl-S-chloro-2,4-disulfamylaniline.

No references cited. 

1. DISULFAMYLANILINE DERIVATIVES SELECTED FROM THE GROUP CONSISTING OF (1) COMPOUNDS HAVING THE FORMULA 